Biocompatible, antithrombogenic materials suitable for reconstructive surgery

ABSTRACT

Biocompatible, highly antithrombogenic material for reconstructive surgery, which is based on poly (L-lactic acid) and or poly (dL-lactic acid) and segmented polyester and urethanes or polyether urethanes.

The invention relates to a new biocompatible, highly antithrombogenicmaterial, of adjustable porosity, compliance and biodegradability, basedon polylactic acid and segmented polyurethanes, for reconstructivesurgery, which can be built up in layers with different compositions andcharacteristics and can be modelled in various shapes by includingreinforcement material. The versatility of the material according to thepresent invention gives it a unique adaptability to the biologicaltissue in which it is incorporated, so that the synthetic material isbuilt up into a new functional entity in reconstructive surgery.

Most synthetic materials used for reconstruction do not have the samemechanical proporties as the specific biological tissue and so do notmatch its specific function. It is known that the specific function oftissue is the trigger of the constant rebuilding of tissue in the growthduring life. The variability of the elastic properties of the materialaccording to the present invention renders it possible to match themechanical properties of most of the biological tissue that has to bereplaced in the body.

As its porosity can be varied, the ingrowth and overgrowth of tissue forcomplete incorporation can be regulated to provide optimum conditionsfor a specific replacement. Its adjustable biodegradability makes itpossible, if desired, to have the synthetic material completely replacedby biological tissue.

Because of the possibility to produce the material in layers ofdifferent compositions, it is also possible to have the characteristicsof each layer match the function of the biological tissue needed torebuild that layer.

Because the material can be modelled by the shapes of mandrels by adipping technique, every form can be produced to match the shape of anorgan to be replaced, such as a tubular neo-artery for example. But alsoa more complex organ such as a trachea can be produced from thissynthetic material, including a reinforcement material in the layers tomaintain its shape during the alternating positive and negativepressures occurring in the trachea and to prevent collapsing. Theconstructive reinforcement material can be made of a different material,for example porous hydroxy apatite, which could induce bone formation.

Due to the biodegradability and high flexibility of thepolylactide-polyurethane porous membranes, these materials can also beused to cover satisfactorily large experimental full-thickness skinwounds. Such membranes can effectively protect these wounds frominfection and fluid loss for a long time.

Thus these combinations give a wide range of new possibilities inreconstructive surgery, all based on the same principle that perfectmatching of the mechanical properties of biological tissue and syntheticmaterials creates one functional unity between biological tissue and thesynthetic material which allows complete incorporation and rebuilding toa new organ. This new composition has been tested in animal experiments,primarily with rabbits, as vascular and tracheal prostheses andartificial skin. In these experiments true biocompatibility and a highdegree of antithrombogenicity of the material was demonstrated. Theexperiments with the trachel prosthesis revealed that quick tissueingrowth from the peritracheal tissue is induced if relatively largepores (100μ) were used on the outside. However, overgrowth of tissue onthe luminal side needed only a thin connective tissue layer to whichepithelium became firmly attached and differentiated. This was achievedwith relatively small pores on the inside (10-20μ). Between the layersof various pore sizes a reinforcement of a spiral bead may be embedded.

This possibility of variation by means of different layers can also beused for the composition of an artificial skin where such functions ascontrolled evaporation, ingrowth of tissue, seeding of epithelial cellsand resistance to outside micro-organism require layers with differentcharacteristics.

More specifically the invention relates to the provision of a materialwhich comprises the following composition in wt. %: poly(L-lactic acid)and/or poly(dL-lactic acid) with a viscosity-average molecular weight inthe range of 2×10⁵ to 5×10⁶, from 5 to 95; and polyester urethane orpolyether urethane, from 5 to 95. Polyester urethane or polyetherurethane may be based on: polytetramethylene adipate,poly(ethyleneglycol adipate), poly(tetramethylene oxide),poly(tetramethylene glycol) or poly(diethyleneglycol adipate,p,p'-diphenylmethane diisocyanate, or toluene diisocyanate, orhexamethylene diisocyanate and 1,4 butanediol or ethylene diamine.

The segmented polyurethane imparts the desired flexibility, strength andantithrombogenity to the material.

The polylactic acid ensures the required modulus and porosity. Byvarying the proportion of polylactic acid, the proposed compliance andtype or porosity can be controlled. As the ester, ether and urethanegroups of polyurethane and the carboxylic group of polylactic acidexhibit poor hydrolytic stability, the material easily breaks down to beeliminated from the body after replacement of the graft by the bodytissues.

In order to increase the rate of material resorption in the body, it isrecommended to use a material which contains at least 20% by weight ofpolylactic acid and polyester urethane, based on hexamethylenediisocyanate, polyethyleneglycol adipate and 1,4-butanediol.

In order to improve antithrombogenic effect, the polyurethane based onpolytetramethylene glycol and p,p'-diphenylmethane may be used.

For the preparation of arteries, arteriovenous shunts or cardiopulmonarybypass, the following compositions of the material, in % by weight, arerecommended:

a. poly(L-lactic acid) or poly(dL-lactic acid), 20; polyether urethane,80.

b. polylactic acid, 30; polyether urethane, 70.

c. polylactic acid, 15; polyether urethane, 85.

For the preparation of veins with a diameter in the range of 1,5 to 10mm, the following composition, in % by weight, is recommended:

a. polylactic acid, 80; polyester urethane, 20.

b. polylactic acid, 70; polyester urethane, 30.

c. polylactic acid, 60; polyester urethane, 40.

For the preparation of tracheal prostheses with a diameter in the rangeof 7-25 mm, the following composition, in % by weight, is recommended:

a. polylactic acid, 50; polyester or polyeter urethane, 50.

b. polylactic acid, 40; polyester or polyeter urethane, 60.

For the preparation of artificial skin having a size in the range of 50to 500 mm by 50 to 500 mm the following composition, in % by weight, isrecommended:

polylactic acid, 20 to 50;

polyester urethane 50 to 80.

The techniques applied for the preparation of tubular grafts and porousmembranes may for example be as follows:

A. Vascular grafts

(a) For higher concentrations of polylactic acid in the mixture:Polylactic acid is dissolved in chloroform at room temperature and 5 to20% by weight of sodium citrate in chloroform ethanol mixture is addedto the solution. Polyurethane is dissolved in tetrahydrofuran so as togive a solution with a concentration in the range of 5.14% by weight.

The solutions of polylactic acid and polyurethane are mixed togetherright before the preparation of the tubes.

The tubes are prepared on a stainless steel mandrel coated withpolytetrafluoroethylene. For this purpose the mandrels are dipped intothe polymer solution and dried at room temperature. Dipping and solventevaporation procedure is repeated to provide the graft with a requiredwall thickness. The grafts are extracted with distilled water andethanol for 5 to 10 hours to remove sodium citrate.

Depending on the concentration of sodium citrate in the polymer solutionand the proportion of polylactic acid, the size of the pores formed inthe grafts is in the range of 5 to 200 μm. In addition the pore size maybe adjusted by changing the polymer concentration in the solution fromwhich the grafts are made. From a more concentrated solution grafts withsmaller pores are obtained. When layers of polymer are deposited on themandrel from solutions with different polymer concentrations compositegrafts are formed having a gradually increasing pore size, suitable forcertain types of implants.

(b) For higher concentrations of polyurethane in the mixture: Polylacticacid is dissolved in tetrahydrofuran at 50° to 90° C. Polyurethane isdissolved separately in tetrahydrofuran. The two solutions are mixedtogether prior to the graft preparation. The concentration of polymer inthe solution is in the range of 5-20% by weight.

Tubes are prepared on stainless steel mandrels coated withpolytetrafluoroethylene (PTFE), the mandrels being dipped into thepolymer solution maintained at a temperature of 60° to 85° C. and nextinto an ethanol distilled water mixture to precipitate the polymer.

Depending on the concentration of polymer in the solution, a porousstructure with different pore size is formed. The structure is composedof thin, elastic polyurethane fibers covered with a thin layer ofpolylactic acid.

As a general rule it is recommended that more concentrated polymersolutions are used for the preparation of grafts having smaller poresizes.

These highly porous polylactic acid-polyurethane materials composed ofrandomly distributed holes and elastic fibers exhibit both radial andlinear compliance.

In all cases the pore-to-matrix ratio by volume can be adjusted from 0to 90 percent.

B. Tracheal Prostheses

Solutions of polymers were prepared as described in Aa and Ab.

After the deposition of 2 to 3 polymer layers on the mandrel, areinforcing bead extruded from polyether urethane or polyamide urethaneis wound tightly around the polymer-coated mandrel and another coatingof polymer is applied. Due to partial dissolution and swelling of thesurface of the reinforcing bead, an excellent, homogenous connectionbetween the bead and the inner and outer walls of the prostheses isformed.

C. Artificial skin

Solutions of polymers are prepared as described in Aa and Ab. A glasscylinder with a rough, sand-blasted surface is dipped into the polymersolution maintained at a temperature of 60° to 85° C., and next into anethanol distilled water mixture to precipitate the polymer.

After washing with water and extraction with ethanol the porous sleeveis removed from the glass mould and cut along its longitudinal axis.

On the upper side of the membrane a polyether urethane or Dow CorningSilastic Medical Adhesive Type A is spread.

The diameter and the length of the glass mold may be in the range of 50to 200 mm and 50 to 200 mm, respectively, depending on the size of thepiece of artificial skin required for implantation.

The proposed material in the form of vascular and tracheal grafts andporous membranes-artificio with various polylactic acidpolyurethanecompositions and porosities, was tested in vivo for anticlottingproperties and tissue ingrowth by implanting into chincilla rabbits andalbino rats weighing 2 to 2.5 kg and 100 to 150 g, respectively.

Histological analysis showed no clotting, connective tissue ingrowth,blood vessels ingrowth, etc.

What is claimed:
 1. Biocompatible, porous, highly antithrombogenicmaterial for reconstructive surgery, which is prepared from mixtures ofpoly(L-lactic acid) and/or poly(dL-lactic acid) and segmented polyesterurethanes or segmented polyether urethanes.
 2. Material according toclaim 1, characterized by the following composition in % byweight:poly(L-lactic acid), 5 to 95, or poly(dL-lactic acid), 5 to 95,and polyester urethane, 5 to 95, or polyether urethane, 5 to
 95. 3.Material according to claim 1, characterized in that the polyesterurethane is the reaction product of:poly(tetramethylene adipate) orpoly(ethyleneglycol adipate) reacted with p,p'-diphenylmethanediisocyanate, toluene diisocyanate or hexamethylene diisocyanate, and1,4-butanediol or ethylene diamine; and the polyether urethane is thereaction product of: poly(tetramethylene oxide), poly(tetramethyleneglycol) or poly(diethyleneglycol adipate) reacted withp,p'-diphenylmethane diisocyanate, toluene diisocyanate or hexamethylenediisocyanate, and 1,4-butanediol, or ethylene diamine.
 4. Biocompatible,porous, highly antithrombogenic, biodegradable articles prepared frommixtures of polylactic acid and segmented polyurethanes, whereincompliance is a function of the ratio between the polylactic acid andthe polyurethane in the mixture.
 5. Biocompatible, porous, highlyantithrombogenic, biodegradable articles prepared from mixtures ofpolylactic acid and segmented polyurethanes, wherein the pore size isfrom 5 to 200 μm and the pore-to-matrix ratio is between 0 and 90percent.
 6. Material according to claim 2, characterized in that thepolyester urethane is the reaction product of: poly(tetramethyleneadipate) or poly(ethyleneglycol adipate) reacted withp,p'-diphenylmethane diisocyanate, toluene diisocyanate or hexamethylenediisocyanate, and 1,4-butanediol or ethylene diamine; and the polyetherurethane is the reaction product of: poly(tetramethylene oxide),poly(tetramethylene glycol) or poly(diethyleneglycol adipate) reactedwith p,p'-diphenylmethane diisocyanate, toluene diisocyanate orhexamethylene diisocyanate, and 1,4-butanediol, or ethylene diamine.